Xu Pu-Ting, Li Yi-Ju, Qin Xue-Jun, Kroner Charles, Green-Odlum Anya, Xu Hong, Wang Tian-Yuan, Schmechel Donald E, Hulette Christine M, Ervin John, Hauser Mike, Haines Jonathan, Pericak-Vance Margaret A, Gilbert John R
Department of Medicine and Center for Human Genetics, Duke University Medical Center, Durham, NC 27710, USA.
Mol Cell Neurosci. 2007 Nov;36(3):313-31. doi: 10.1016/j.mcn.2007.06.009. Epub 2007 Jul 24.
APOE4 allele is a major risk factor for late-onset Alzheimer disease (AD). The mechanism of action of APOE in AD remains unclear. To study the effects of APOE alleles on gene expression in AD, we have analyzed the gene transcription patterns of human hippocampus from APOE3/3, APOE3/4, APOE4/4 AD patients and normal control using Serial Analysis of Gene Expression (SAGE). Using SAGE, we found gene expression patterns in hippocampus of APOE3/4 and APOE4/4 AD patients differ substantially from those of APOE3/3 AD patients. APOE3/4 and APOE4/4 allele expression may activate similar genes or gene pools with associated functions. APOE4 AD alleles activate multiple tumor suppressors, tumor inducers and negative regulator of cell growth or repressors that may lead to increased cell arrest, senescence and apoptosis. In contrast, there is decreased expression of large clusters of genes associated with synaptic plasticity, synaptic vesicle docking and fusing and axonal/neuronal outgrowth. In addition, reduction of neurotransmitter receptors and Ca2+ homeostasis, disruption of multiple signal transduction pathways, loss of cell protection, and perhaps most notably, mitochondrial oxidative phosphorylation/energy metabolism are associated with APOE3/4 and APOE4/4 AD alleles. These findings may help define the mechanisms that APOE4 contribute that increase risk for AD and identify new candidate genes conferring susceptibility to AD.
APOE4等位基因是晚发型阿尔茨海默病（AD）的主要风险因素。APOE在AD中的作用机制仍不清楚。为了研究APOE等位基因对AD中基因表达的影响，我们使用基因表达序列分析（SAGE）分析了APOE3/3、APOE3/4、APOE4/4的AD患者以及正常对照者的人类海马体的基因转录模式。通过SAGE，我们发现APOE3/4和APOE4/4的AD患者海马体中的基因表达模式与APOE3/3的AD患者有很大不同。APOE3/4和APOE4/4等位基因表达可能激活具有相关功能的相似基因或基因库。APOE4的AD等位基因激活多种肿瘤抑制因子、肿瘤诱导因子以及细胞生长的负调节因子或阻遏物，这可能导致细胞停滞、衰老和凋亡增加。相比之下，与突触可塑性、突触小泡对接和融合以及轴突/神经元生长相关的大量基因簇的表达减少。此外，神经递质受体减少和Ca2+稳态失衡、多种信号转导途径的破坏、细胞保护作用丧失，也许最值得注意的是，线粒体氧化磷酸化/能量代谢与APOE3/4和APOE4/4的AD等位基因有关。这些发现可能有助于明确APOE4增加AD风险的作用机制，并识别出赋予AD易感性的新候选基因。
